Hepatitis E virus (HEV) has been recognized as an important cause of human hepatitis worldwide, since it was shown to be responsible for water-born outbreaks in Asia two decades ago. The virus is now known to cause clinical and subclinical hepatitis in the United States, Europe and other countries from a zoonotic reservoir in pigs and other animals. Since HEV infection typically causes silent infection in adults, it can also be transmitted by blood transfusion from asymptotic donors. However, despite a few case reports from Europe and Japan and the detection of HEV RNA in plasma pools, the risk of transfusion transmission in the US and elsewhere is unknown. HEV infection in immunocompromised patients, pregnant women and patients with liver disease can have serious morbidity or mortality. In this study we will estimate the risk of transmission of HEV by blood product transfusion by studying three populations. We will study the prevalence of anti-HEV IgM and HEV RNA in a serum repository obtained from 5,000 Chinese blood donors with elevated liver enzymes who were not infected with hepatitis B and C. Secondly, we will measure the rate of sero-conversion among a sample of 11,532 patients enrolled in the NHLBI-funded FACTS study in the early 1990's. In this study, 9,294 patients were transfused with blood products from over 120,000 donors and 2,238 similar subjects were not transfused, who will serve as controls. Third, we will measure the risk of transfusion transmission of HEV in 3,575 patients with RADAR study. The RADAR study is a linked donor-recipient repository. We will test the donors linked to any patients who have sero-converted after their transfusion for evidence of active HEV infection, i.e. HEV RNA and anti-HEV IgM. Strains of HEV from donors and recipients will be sequenced when possible. We will also test 100 mini-pools of 50 plasma samples, i.e. 5,000 individual samples, from the RADAR repository that are unlinked to a recipient. Positive pools will be re-tested sequentially to resolve infectivity of an individual door. These three inter-related studies will allow us to estimate the level of risk of transmission of HE by transfusion of blood products. If this risk is confirmed, our data can be used to develop policies for screening donors to prevent the recent documented serious clinical consequences of HEV infection among high risk patients.